erbB3 is a single pass type transmembrane protein which belongs to epidermal growth factor receptor (EGFR) family (Non-Patent Documents 1, 2, and 3). The three-dimensional structure of erbB3 is similar to that of EGFR, Her2, and erbB4, and the extracellular domain thereof is constituted with four-domain structure including domains 1, 2, 3, and 4 from N-terminal. EGFR family molecules other than erbB3 have intracellular kinase domains, and kinase activity is performed when their receptors are activated, but the intracellular domain of erbB3 does not have the kinase activity.
Regarding activation of erbB3, two pathways are known which include 1. a signaling cascade in which erbB3-specific ligand heregulin binds to erbB3, erbB3 is phosphorylated due to other EGFR family forming a hetero dimer with erbB3, and then a phosphatidyl inositol-3 phosphate kinase (PI3 kinase) and Akt are activated, and 2. a signaling cascade in which EGFR family (EGFR, Her2, or the like) other than erbB3 is activated due to the binding or overexpression of the ligand, erbB3 is consequently phosphorylated, and then the PI3 kinase and Akt are activated.
The results obtained by exhaustively analyzing the affinity between the intracellular domain of EGFR family molecules and signaling proteins by using protein arrays strongly suggest that among the EGFR family molecules, erbB3 particularly shows high affinity with the PI3 kinase and plays an important role in activating the PI3 kinase (Non-Patent Document 4). In recent years, erbB3 has been reported to be involved in making cancer to be resistant to an EGFR inhibitor (Non-Patent Documents 5 and 6).
It has been clarified that in drug-resistant tumors, tumor cells keep growing in the presence of a drug since a hepatocyte growth factor receptor (HGFR or Met) causes phosphorylation of erbB3 (Non-Patent Document 5) or since Met increases the expression of erbB3 (Non-Patent Document 6).
There are several reports on correlation between the expression of erbB3 and prognosis of cancer. Chen et al. (Non-Patent Document 7) select 5 genes (DUSP6, MMD, STAT1, ERBB3, and LCK) highly correlated with the prognosis of lung cancer, based on the results of array analysis, and erbB3 is included in the selected genes.
In immunohistological analysis, the expression of erbB3 is reported to be a poor prognostic factor of lung cancer (Non-Patent Document 8). Muller-Tidow et al. (Non-Patent Document 9) investigated kinases relating to metastasis of lung cancer by array analysis, and as a result, erbB3 was identified to be a third gene highly correlated to the risk of distant metastasis after INSR and NTRK1. The expression of erbB3 is reported to be a poor prognostic factor in breast cancer (Non-Patent Document 10) and ovarian cancer (Non-Patent Document 11) in addition to lung cancer.
Regarding anti-erbB3 antibodies, an antibody which inhibits binding of heregulin to erbB3 (Non-Patent Document 12), an antibody which does not bind with erbB1 and erbB2 but specifically binds with erbB3 (Patent Document 1), an antibody which inhibits heregulin-dependent erbB2-erbB3 interaction (Patent Document 2), an antibody which binds with the extracellular domain of erbB3 (Patent Document 3), and an antibody which binds to a domain 1 of erbB3 to inhibit heregulin-dependent phosphorylation of erbB3 (Patent Document 4) are reported.